(Hypertension. 1997;29:570-575.)
© 1997 American Heart Association, Inc.
Articles |
Cyclosporin A Increases Nitric Oxide Activity In Vivo
the Departments of Nephrology and Hypertension (E.S.G.S., H.A.K., T.J.R.) and of Hematology (F.G. de G.), University Hospital Utrecht (Netherlands), and Cardiovascular Research, University Hospital, Bern, Switzerland (T.F.L.)A
The use of cyclosporine is complicated by its vasoconstrictive actions. In vitro cyclosporine has been associated with both decreased endothelium-dependent vasodilatation and increased nitric oxide activity. We studied the interaction between cyclosporine and endothelium-derived nitric oxide in seven healthy volunteers. Using venous-occlusion plethysmography, we measured forearm blood flow during intra-arterial infusion of serotonin, which in the concentrations used is a selective agonist of endothelial nitric oxide release, or NG-monomethyl-L-arginine, a specific inhibitor of nitric oxide synthase, during coinfusion of saline or cyclosporine (75 µg/min), respectively. During coinfusion of cyclosporine, forearm blood flow increased on maximal serotonin infusion from 2.9 (SE, 0.2) to 8.1 (0.9) mL/100 mL per minute in forearm tissue, which was significantly higher than the increase during saline coinfusion (3.0 [0.3] to 6.0 [0.5]; P<.05). Cyclosporine infusion during a "free" nitric oxide system had no effect on basal forearm blood flow, but it significantly decreased forearm blood flow (21.7 [2.8]%; P<.05) during fixed nitric oxide activity. These data suggest that acute administration of cyclosporine enhances both basal and receptor-stimulated nitric oxide activity. The mechanism is not clear but may include cyclosporine-induced shear stress as well as direct effects of cyclosporine. The latter was supported by our observation that gene expression of the enzyme nitric oxide synthase III was enhanced by approximately 50% after coincubation with cyclosporine. In conclusion, the present observation demonstrates that nitric oxide constitutes an important regulating mechanism that protects against cyclosporine-associated vasoconstriction in vivo.
Key Words: cyclosporine • nitric oxide • serotonin • nitric oxide synthase
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